Project Summary/Abstract Hemorrhage following traumatic injury is estimated to be responsible for over 40% of all trauma-related deaths. Ongoing traumatic blood loss is complicated by the well-known ?lethal triad? of coagulopathy, hypothermia and acidosis which results in further unbridled hemorrhage. Uncontrolled bleeding, resultant shock and organ dysfunction remain the leading causes of early in-hospital mortality. Despite advances in trauma resuscitation, a paucity of therapeutic interventions are available early enough to reduce the downstream morbidity and mortality attributable to hemorrhage, shock and coagulopathy. The underlying principle of current resuscitation practice in the hospital focuses on preventing or reversing the effects of coagulopathy with the early use of a balanced component transfusion strategy. This reconstituted strategy has been coined ?whole blood-like? resuscitation despite being inferior from a compositional and hemostatic standpoint relative to whole blood. Whole blood use continues today in specific environments and patient populations and is thought to provide the bleeding patient the identical components they are losing with maximal resuscitative and hemostatic effects. Whole blood has also been postulated to improve microcirculatory hemodynamics, reduce the ?storage lesion? effect and minimize donor exposure risks. Due to the time sensitive nature of the treatment of hemorrhage, the ideal resuscitation intervention would entail use of a blood product containing all essential hemostatic components, closest to time of injury, where prevention or reversal of the devastating downstream consequences of shock and coagulopathy can occur. We hypothesize that the initiation of whole blood resuscitation in the prehospital setting with continuation thru the in-hospital acute resuscitation phase of care will significantly reduce the morbidity and mortality attributable to hemorrhagic shock post- injury as compared to standard prehospital and in-hospital resuscitation practice. This hypothesis will be tested by addressing the following specific aims: Specific Aim I: Determine the feasibility, most appropriate study population and outcomes of a study protocol that will lead to a large multicenter clinical trial designed to evaluate the effectiveness of prehospital thru in- hospital LTLR-WB as compared to standard care practice in patients at risk of hemorrhagic shock. Specific Aim II: Determine if prehospital thru in-hospital LTLR-WB reduces multiple organ dysfunction, presenting coagulopathy, 24 hour resuscitation requirements and early mortality as compared to standard of care prehospital and in-hospital resuscitation in patients at risk of hemorrhagic shock. Specific Aim III: Determine the primary drivers by which prehospital thru in-hospital LTLR-WB improves clinical, resuscitative and hemostatic outcomes as compared to standard of care prehospital and in-hospital resuscitation in patients at risk of hemorrhagic shock.